In 1991 a new type of G-protein-coupled receptor (GPCR) was cloned, the type 1a metabotropic glutamate (mGlu) receptor, which, despite possessing the defining seven-transmembrane topology of the GPCR superfamily, bore little resemblance to the growing number of other cloned GPCRs. Subsequent studies have shown that there are eight mammalian mGlu receptors that, together with the calcium-sensing receptor, the GABAB receptor (where GABA is γ-aminobutyric acid) and a subset of pheromone, olfactory and taste receptors, make up GPCR family C. Currently available data suggest that family C GPCRs share a number of structural, biochemical and regulatory characteristics, which differ markedly from those of the other GPCR families, most notably the rhodopsin/family A GPCRs that have been most widely studied to date. This review will focus on the group I mGlu receptors (mGlu1 and mGlu5). This subgroup of receptors is widely and differentially expressed in neuronal and glial cells within the brain, and receptor activation has been implicated in the control of an array of key signalling events, including roles in the adaptative changes needed for long-term depression or potentiation of neuronal synaptic connectivity. In addition to playing critical physiological roles within the brain, the mGlu receptors are also currently the focus of considerable attention because of their potential as drug targets for the treatment of a variety of neurological and psychiatric disorders.

Prostaglandins E1 and E2 increased the sensitivity of glycolysis to insulin in the isolated stripped soleus muscle of the rat, but prostaglandin F2 alpha had no effect. Indomethacin, which inhibits prostaglandin formation, markedly decreased the sensitivity of glycolysis to insulin. These findings suggest that prostaglandins of the E series increase the sensitivity of muscle glycolysis to insulin in vivo.

Phosphorus nuclear magnetic resonance (31P-NMR) spectroscopy was used to assess the effects of hypoinsulinemia on skeletal muscle during contraction in vivo. Five groups of rats were studied: age-matched (CONA) and weight-matched (CONW) nondiabetic controls; rats given streptozotocin 21 days before study (UD); diabetic rats treated with insulin for 21 days (ITD); and insulin-treated diabetic rats with insulin treatment withheld for 72 h before study (IWD). Both UD and IWD had similar alterations in plasma substrate concentrations and an impairment in the rate of glycogen resynthesis after the stimulation protocol compared with ITD, CONA, and CONW. Pyruvate oxidation was decreased by 30-40% in mitochondria isolated from gastrocnemius of the UD group, whereas no significant decrease was observed for mitochondria from the IWD (or ITD) group(s). In UD, maintenance of gastrocnemius muscle isometric twitch tension at 1 Hz required exaggerated decreases in phosphocreatine (PCr) concentration and pH; at 5 Hz, muscle performance declined significantly, and intracellular pH decreased to lower values than observed for the control groups; during recovery, no impairment of PCr resynthesis was observed. We conclude that in skeletal muscle of UD 1) at 1 Hz there is an increased reliance on glycolytic mechanisms of ATP resynthesis and 2) at 5 Hz force failure may occur because of the decreased rate of pyruvate utilization.

This study determined whether the sensitivity of glucose metabolism to insulin in skeletal muscle varies during a 24-h period. Soleus muscles were isolated from ad libitum-fed rats killed at 0900, 1600, 2100, and 0300. The animal house was illuminated between 0800 and 2000. The sensitivities of glycolysis (which is an excellent index of glucose transport) and glycogen synthesis to insulin were greatest in muscles isolated at 0900 and 2100. Marked decreases in sensitivities of both processes to insulin were observed in muscles isolated at 0300 and 1600, which are times halfway through the feeding and postabsorptive periods, respectively. Hence, this study demonstrates circadian changes in the sensitivity of glucose utilization by skeletal muscle to insulin, which may be important in control of blood glucose concentration. Glycogen levels in skeletal muscles were highest at 0300 and lowest at 2100; hepatic glycogen content reached a peak at 0900, and the lowest content was measured at 2100. The liver glycogen level was increased by only 15% midway into the feeding period (i.e., 0300). This suggests that muscle glycogen may act as a temporary store of glucose residues during the feeding period; it stores glycogen in the first half of the feeding period but during the second half some muscle glycogen is converted to lactate, which acts as a precursor for hepatic gluconeogenesis.

The mechanisms involved in Ca2+ mobilization evoked by the muscarinic cholinoceptor (mAChR) agonist carbachol (CCh) and N‐methyl‐d‐aspartate (NMDA) in cerebellar granule cells have been investigated. An initial challenge with caffeine greatly reduced the subsequent intracellular Ca2+ concentration ([Ca2+]i) response to CCh (to 45 ± 19% of the control), and, similarly, a much reduced caffeine response was detectable after prior stimulation with CCh (to 27 ± 6% of the control). CCh‐evoked [Ca2+]i responses were inhibited by preincubation with thapsigargin (10 µM), 2,5‐di(tert‐butyl)‐1,4‐benzohydroquinone (BHQ; 25 µM), ryanodine (10 µM), or dantrolene (25 µM). BHQ pretreatment was found to have no effect on the sustained phase of the NMDA‐evoked [Ca2+]i response. Both CCh (1 mM) and 1‐aminocyclopentane‐1S,3R‐dicarboxylic acid (ACPD; 200 µM) evoked a much diminished increase in [Ca2+]i in granule cells pretreated with CCh for 24 h compared with vehicle‐treated control cells (CCh, 23 ± 14%; ACPD, 27 ± 1% of respective control values). In contrast, a 24‐h CCh pretreatment decreased the subsequent inositol 1,4,5‐trisphosphate (InsP3) response to CCh to a much greater extent compared with responses evoked by metabotropic glutamate receptor (mGluR) agonists; this suggests that the former effect on Ca2+ mobilization represents a heterologous desensitization of the mGluR‐mediated response distal to the pathway second messenger. Furthermore, [Ca2+]i responses to caffeine and NMDA were unaffected by a 24‐h pretreatment with CCh. This study indicates that ryanodine receptors, as well as InsP3 receptors, appear to be crucial to the mAChR‐mediated [Ca2+]i response in granule cells. As BHQ apparently differentiates between the CCh‐ and NMDA‐evoked responses, it is possible that the directly InsP3‐sensitive pool is physically different from the ryanodine receptor pool. Also, activation of InsP3 receptors may not contribute significantly to NMDA‐evoked elevation of [Ca2+]i in cerebellar granule cells. A model for the topographic organization of cerebellar granule cell Ca2+ stores is proposed.